Integrating transcriptome and metabolome variability to reveal pathogenesis of esophageal squamous cell carcinoma

Esophageal Squamous Cell Carcinoma (ESCC) is an aggressive malignancy, leading to more than 250,000 deaths in China every year. However, the pathogenesis of ESCC remains unclear, which hinders the diagnosis and treatment of the disease in clinic. To elucidate underlying mechanism and identify potential biomarkers, an integrative strategy of combining transcriptome and metabolome has been implemented to find potential causal genes and metabolites for ESCC. At the transcriptional level, dysregulated genes in ESCC patients were identified and pathway enrichment analysis discovered tyrosine metabolic pathway as a promising target. Subsequently, up- and down-stream metabolites of tyrosine pathway were explored through targeted metabolome approach. Five metabolites, i.e. phenylalanine, 4-hydroxyphenyllactic acid, 3,4-dihydroxyphenylalanine, 3,4-dihydroxyphenylacetic acid and tyrosine were identified as diagnosis biomarkers for ESCC and metastatic ESCC patients. A biological model incorporating both transcriptional and metabolic dysregulation was also established to illustrate the potential mechanism of tumorigenesis and metastasis for ESCC. Integrative transcriptomics and metabolomics analysis suggested that tyrosine pathway was essential for the tumorigenesis and metastasis of ESCC primarily through altering immune response and regulating tumor microenvironment. This research sheds light on the pathogenesis of ESCC and discovers potential biomarkers for the diagnosis of the disease.